SR 143 begins at the entrance to Camp Peary in York County north of Williamsburg. The state highway heads south as Merrimac Trail, a four-lane
divided highway that meets I-64 at a
partial cloverleaf interchange. SR 143 heads south through a forested area and meets the northern end of
SR 132, which provides access to
Colonial Williamsburg and, via
Colonial Parkway,
Jamestown and
Yorktown. The state highway crosses Queen Creek into the city of Williamsburg and meets the northern end of
SR 5 (Capitol Landing Road). East of the SR 5 intersection, SR 143 reduces to a two-lane undivided road, crosses Colonial Parkway with no access, and re-enters York County by crossing an unnamed creek. SR 143 becomes a five-lane road with a
center left-turn lane at its intersection with
SR 162 (2nd Street). The state highway heads southeast and enters James City County at its intersection with SR 641 (Penniman Road). SR 143 begins to closely parallel the north side of
CSX's
Peninsula Subdivision, which is itself paralleled by US 60 (Pocahontas Trail) to the south; the center left-turn lane becomes a left-turn lane exclusively for the eastbound direction of the highway. The two highways have mirror-image partial cloverleaf interchanges with
SR 199 (Humelsine Parkway) as they re-enter York County. SR 143 passes between Williamsburg Country Club to the north and
Busch Gardens Williamsburg to the south; the state highway does not have access to the theme park. Just east of the park, the westbound direction of the state highway receives an exit ramp from I-64. SR 143 continues east into James City County as a four-lane undivided highway that closely parallels I-64 to the north and the railroad to the south while passing through a forested area. The state highway receives a ramp from eastbound I-64 shortly before crossing Mill Run into the city of Newport News, where the highway's name changes to Jefferson Avenue. Just east of the stream, there are ramps from eastbound SR 143 to eastbound I-64 and from westbound SR 143 to westbound I-64 as the state highway crosses to the north side of the Interstate. SR 143 intersects
SR 238 (Yorktown Road), which provides access to and from I-64 in the direction of Hampton, near the
Lee Hall area of the city. The state highway passes through
Newport News Park and crosses the Lee Hall Reservoir before intersection
SR 105 (Fort Eustis Boulevard) near
Fort Eustis. The intersection is just east of SR 105's interchange with I-64; the ramps to and from westbound I-64 for access to SR 105 in the direction of Yorktown connect with SR 143 north and south of the interchange, respectively. SR 143 veers away from I-64 and expands to a six-lane divided highway at Kings Ridge Drive. The state highway intersects
SR 173 (Denbigh Boulevard) east of the
namesake community and north of
Newport News/Williamsburg International Airport, which is accessed by Bland Boulevard. Southeast of the airport, SR 143 crosses to the south side of I-64 at a
cloverleaf interchange adjacent to
Patrick Henry Mall. The state highway intersects
SR 171 (Oyster Point Road) and passes through an industrial and commercial area that includes the
Jefferson Lab (Thomas Jefferson National Accelerator Facility) and the
City Center at Oyster Point. South of the city center, SR 143 intersects J. Clyde Morris Boulevard, which heads northeast as part of US 17 toward Yorktown and west as
SR 312. SR 143 and US 17 run concurrently southeast through junctions with
SR 306 (Harpersville Road) and
SR 152 (Main Street) before diverging at Mercury Boulevard, a major east–west thoroughfare that carries US 258 and provides access to the
James River Bridge. This intersection is also the northern terminus of
SR 32. SR 143 becomes a four-lane undivided highway at 40th Street, which is used to access
SR 351 (39th Street). SR 351 passes over SR 143 just to the north of SR 143's partial interchange with
I-664 (Hampton Roads Beltway), which includes ramps from eastbound SR 143 to southbound I-664 and from northbound I-664 to SR 143. The state highway becomes two lanes at 34th Street and maintains that profile southeast to 27th and 28th Streets, onto which the highway turns northeast as a
one-way pair, with eastbound following 27th Street and westbound using 28th Street. This one-way pair is just north of US 60's one-way pair on 25th and 26th Streets. The one-way pair ends at Salters Creek, where the highway comes together as a four-lane divided highway passes through a sliver of the city of Hampton. SR 143 enters Hampton for good at Pear Avenue, where the highway continues as Victoria Boulevard. SR 143 follows Victoria Boulevard through the
Wythe and
Kecoughtan neighborhoods of Hampton. Within the latter neighborhood, the state highway intersects US 60; the state highway joins the U.S. Highway north on Kecoughtan Road then east on Settlers Landing Road. The two highways meet the southern end of
SR 134 (Armistead Avenue) and head as a two-lane divided street through downtown Hampton, which contains
St. John's Episcopal Church and the
Virginia Air and Space Center. SR 143 and US 60 become four lanes again to cross the
Hampton River and pass along the northern edge of the campus of
Hampton University. The two highways diverge at their
diamond interchange with I-64 (Hampton Roads Beltway), which US 60 joins to cross
Hampton Roads via the
Hampton Roads Bridge-Tunnel to
Norfolk. SR 143 continues southeast along two-lane County Street, turns southwest onto Libby Street for one block, then turns south on Mellen Street and intersects
SR 169 (Mallory Street) within the
Phoebus neighborhood. The state highway crosses the Mill Creek estuary as Ingalls Road and reaches its eastern terminus at its junction with US 258's (Mercury Boulevard) northern terminus at the entrance to Fort Monroe. ==Major intersections==